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Gazing into the Crystal Ball of Pain Research

The future looks promising for the understanding and treatment of pain. Image credit: tiero/123RF Stock Photo.

Editor’s Note: The third North American Pain School (NAPS) took place June 24-28, 2018, in Montebello, Quebec, Canada. This educational initiative brought together leading experts in pain research and management to provide 30 trainees–part of the up-and-coming generation of pain researchers–with scientific education, professional development and networking experiences. Six of the trainees were also selected to provide first-hand reporting from the event, including summaries of talks presented at the meeting. Here, Donald Iain MacDonald, a PhD student at University College London, UK, summarizes a talk delivered by Allan Basbaum, a pain researcher at the University of California, San Francisco. Basbaum’s talk focused on what the future of pain research and treatment looks like.

Allan Basbaum, native Montrealer and now a renowned pain researcher at the University of California, San Francisco, returned to Quebec this past summer for the North American Pain School to give his prognosis on the future of pain research and treatment. With a ten-year stint as the editor-in-chief of the journal PAIN under his belt, there are few better-qualified fortune-tellers when it comes to predicting where the pain field is headed in the years to come. So what did Basbaum’s crystal ball have to say?

Precision medicine
After talking at length about how painkillers work, Basbaum said that a particularly perceptive listener once asked him: “But how does the aspirin know where to go?”

Of course, the aspirin doesn’t know where to go—and that’s why painkillers have side effects. Think about your last trip to the dentist. A local anesthetic injected into the mouth certainly blocks the pain one feels as a rotten tooth is removed. But it blocks other sensations too. Local anesthetics work by blocking sodium ion channels, a family of proteins that drive electrical activity in the nerves that carry sensory information from the body to the brain. By inhibiting that activity, these local anesthetics block the senses of touch, itch, and pain in the injected area.

There are nine different “flavors” of sodium channels. In 2005, researchers at Cambridge University in the UK discovered a Pakistani family who had complete insensitivity to pain from birth, but whose sensation of touch was normal. These patients had a mutation in one specific flavor of sodium channel called Nav1.7, which was quickly christened the “off-switch” for pain.

The novel discovery suggested a new strategy: instead of blocking all the sodium channels, make a drug that blocks just Nav1.7. Now you would have something that blocks only pain, and with few side effects since it would leave all the other flavors of sodium channels untouched. Although it has proven difficult to make such specific blockers, and clinical trials have yet to bear fruit, this precision approach of targeting particular molecules looks likely to continue as a popular strategy for pain treatment. For Basbaum, there remains a whole menagerie of molecules to inhibit for particular kinds of pain, including a number of different families of ion channel proteins.

Antibodies
Those molecules need not be targeted with so-called “small molecule” drugs that come straight from the chemist’s lab, however. According to Basbaum, antibodies—proteins built by the immune system—look to have an exciting future, particularly in the treatment of arthritis and migraine pain.

Arthritis, specifically osteoarthritis, is among the most common causes of chronic pain. In osteoarthritis, inflammation and tissue damage trigger the release of molecules that activate pain-sensing neurons. One particularly nasty ingredient of the so-called “inflammatory soup” is nerve growth factor, or NGF. Antibodies that neutralize NGF can give up to 50% pain relief from arthritis pain, over four months. Worryingly, in some patients this approach caused damage to other joints, although this seemed the result of interactions with other drugs the patients were taking at the time. Although the trials were temporarily halted because of these concerns, they have now been restarted; hopefully, the concern about adverse side effects has been addressed.

Another promising example is migraine, which affects 17% of women, and 6% of men. Migraine results from electrical firing in nerves containing a molecule called calcitonin gene-related peptide, or CGRP, and antibodies directed against CGRP have been shown to reduce one-third of migraines. Basbaum stressed that these antibodies have come straight out of basic research—that is, laboratory studies in animals—which highlights the importance of work in non-human species.

“Biased” opioids
In 1989, Basbaum organized a conference in Berlin to put together a book entitled “The Pharmacotherapy of Pain: Beyond Morphine.” Even as the Berlin Wall came down around them, the conference-goers dropped the “Beyond Morphine” part of the title. Today, with an opioid epidemic raging throughout North America, it seems we are further and further from kicking the morphine habit.

Opioids work by binding to proteins called opioid receptors on the surface of cells. But opioids are “promiscuous” drugs because they bind to different “flavors” of opioid receptor all over the body and in different areas of the brain. This causes myriad side effects, including dependency, addiction, constipation and slowing of breathing.

For some researchers, the solution is to make opioids that are “biased” to act in particular areas of the nervous system and at particular flavors of the opioid receptor. Recently, scientists have designed opioids that act on specific molecular pathways to give pain relief in animals, without effects on breathing or the gut. Yet the biased opioids developed so far may still carry the risk of addiction.

Alternatively, the development of drugs that do not penetrate the blood-brain barrier (a border that separates the blood circulation from the brain), but instead act selectively outside of the brain, could have useful effects without the adverse consequences that occur when a drug reaches the brain. Anyone who has ever had diarrhea may have taken one such drug without realizing it: Immodium is an opioid that stays in the gut and causes constipation. In this case, constipation is the desired consequence, rather than a side effect.

Cell transplantation
While running the journal PAIN, Basbaum had many favorite pieces of cover art. One was a sculpture by a patient with complex regional pain syndrome (CRPS; see related RELIEF feature article on this condition here). The sculpture depicted a foot stabbed full of scalpels. For this kind of excruciating pain caused by nerve injury (neuropathic pain), the best treatment is gabapentin, a drug that works in 30% of people, 30% of the time.

In Basbaum’s view, the path forward is to consider neuropathic pain not as a symptom, but as a disease of the nervous system whose manifestation is pain. He suggested that people should think of pain as being like epilepsy. Epilepsy results from a loss of a class of neurons in the brain that make a neurotransmitter called GABA; these GABA neurons normally inhibit the electrical activity of nerve cells. Basbaum likened epilepsy to an orchestra without a conductor: the brain cells “fire” like crazy, with no rhythm or order, lacking their inhibitory conductor to keep them in check. Perhaps pain is like this too: in chronic pain, the inhibitory GABA neurons that dampen pain aren’t there to control the barrage of electrical activity in the brain that can culminate in an experience of pain.

To test this idea, Basbaum’s lab transplanted early-stage inhibitory GABA neurons into the spinal cord of mice with experimental chronic pain. Amazingly, the adult spinal cord accepted the transplant, the GABA neurons integrated into the tissue, and this quieted the pain in the animals. For Basbaum, such cell transplantation therapy might prove useful in humans with intractable chronic pain.

Pain in the brain
Open any textbook of neuroscience in the world and you’ll be confronted with diagrams purporting to explain how the pain system works. For Basbaum, these diagrams look eerily like the famous drawing by the 17th century French thinker René Descartes—fire burns a man’s foot, which pulls a wire that rings a bell in the brain. In this view, pain is just an unpleasant reaction to a stimulus; if you cut or turn off the wire that leads up to the brain, you turn off the pain. Implicit in the new therapies that block sodium channels, neutralize NGF molecules, or increase the activity of nerve cells in the spinal cord that inhibit pain is the idea that if you just cut off the input to the brain, the pain will go away.

Yet another favorite PAIN cover of Basbaum’s is a painting by a patient with chronic pain due to stroke. The patient usually painted with red backgrounds, but when she painted with blue backgrounds, the blue color triggered pain. So relieving pain isn’t as simple as silencing the nerves that bring sensory information to the brain; an understanding of the complex emotional and cognitive components of pain, and how the brain gives rise to them, is also required.

For a window into the experience of pain, researchers need a window into the electrical activity in the brain during that experience. That is what Basbaum’s lab is now pursuing—his team looks through the skull into the brains of mice and sees neurons that have been engineered to flash green when they are firing. Over many months, Basbaum’s group can watch the activity of the “brain in pain” to better understand the pathways and circuits there that contribute to pain. And while these windows into the skull can never reveal exactly what the experience of pain is, they can help pinpoint what is happening in the nervous system when pain arises.

So, as well as gazing into crystal balls, it seems in the years to come that pain researchers will be gazing into crystal skulls to understand the future of pain.

Donald Iain MacDonald is a PhD student at University College London, UK.

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